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Abstract

Background

Kawasaki disease is a systemic vasculitis and may affect cerebral function acutely.
The aim of the present study was to measure a number of behaviour and social parameters
within a cohort of Kawasaki disease patients.

Methods

Parents of children with past diagnosis of Kawasaki disease were recruited to complete
several behaviour screening questionnaires. Sixty five sets of questionnaires relating
to the patient cohort received were eligible for inclusion. Two control groups were
used, a hospital (HC) control and a sibling control (SC) group.

Results

40% of the Kawasaki disease group showed elevated internalising scores in the clinical
or borderline-clinical range. This compared with 18% of hospital controls and 13%
of sibling controls. Additionally, the Kawasaki disease (KD) group were shown to be
experiencing greater overall total difficulties when compared with the controls (KD
13.7, HC 8.6, SC 8.9). The KD group attained higher behavioural scores within the
internalising sub-categories of somatic problems (KD 61, HC 57, SC 54) and withdrawn
traits (KD 56, HC 53, SC 51). The KD group were also shown to be suffering more thought
problems (KD 57, HC 53, SC 50) compared with the controls. Further difficulties relating
to conduct (KD 3.3, HC 1.4) and social interactions (KD 6.7, HC 8.3) are also highlighted
for the KD group compared with hospital controls. Positron emission tomograms were
performed on nine patients to investigate severe behavioural problems. Three showed
minor changes, possibly a resolving cerebral vasculopathy.

Conclusion

Kawasaki disease can be associated with significant behavioural sequelae. This is
an important consideration in the long-term follow up and referral to a clinical psychologist
may be necessary in selected patients.

Keywords:

Background

In 1967, Tomisaku Kawasaki first described an illness in children called 'acute febrile
mucocutaneous lymph node syndrome' [1]. It has now become more commonly known as Kawasaki disease. The diagnostic criteria
according to the Centres for Disease Control (Atlanta) are laid out below. Fever of
5 days plus 4 out of the 5 remaining criteria [2], or fever plus coronary artery aneurysms at echocardiography and 3 additional criteria
are generally required for a diagnosis of Kawasaki disease to be made [3] (see table 1).

Cardiac complications can occur which include coronary artery aneurysms, which have
been documented as developing during the illness in 25% of patients treated with aspirin
alone (determined at echocardiography) [3,4]. Treatment with intravenous gammaglobulin and aspirin has been shown to reduce this
incidence considerably [5,6].

Pathologically, Kawasaki disease is a multisystem vasculitis affecting small and medium
sized arteries. Inflammation is progressive, initially mild affecting only the subendothelium
and progressing to a severe panarteritis of the coronary arteries. Injured arteries
are weakened and thus aneurysms may form as a result [3].

Neurological and psychological complications associated with Kawasaki disease have
also been noted, although reports in this area are limited. Neurological complications
include aseptic meningitis occurring in 26–50% of cases as well as facial nerve palsy,
sensorineural hearing loss, hemiplegia, cerebral infarction and severe lethargy, which
have all been reported in various case studies [3-6]. Amano and Hazama have examined histological specimens from 30 Kawasaki disease patients
and found evidence of the occurrence of endoarteritis and periarteritis within the
brain [3] and it is likely that many of the CNS complications are secondary to such a process
of cerebral vasculitis [8].

Extreme irritability is a well documented observation seen in children during the
acute phase of the illness, which generally resolves after treatment. However, a recent
study performed by King and workers have reported that behavioural problems may develop
or persist once the acute phase of the illness has passed and then continue for months
or years after the initial illness [7]. The study consisted of 32 patients with Kawasaki disease in the USA and used siblings
as controls. They demonstrated that post acute Kawasaki disease patients had a significantly
greater tendency to internalising and attentional behavioural problems, although no
firm aetiology was uncovered [7]. However, this study was somewhat limited as it was carried out on a relatively small
cohort and did not include a control group of patients that had been hospitalised
for a similar time period.

It is these behavioural sequelae that we are interested in as we have documented many
cases in clinic of reported behavioural problems persisting for months and years after
the initial episode of Kawasaki disease.

We initially set out to screen for potential behavioural problems within a British
patient cohort. 123 children with a past diagnosis of Kawasaki disease reviewed in
a long term Kawasaki disease follow up clinic were included. Parents were asked at
time of their visit to answer a series of questions relating to behaviour and certain
aspects of their child's disease. Additionally, 142 questionnaires used by a national
Kawasaki disease parent support group were reviewed retrospectively. All the data
was collected between 1996–1999, with 265 children being reviewed in total. The questions
in clinic and within the help group questionnaire were derived from Rutter's B questionnaire,
with the aim to identify significant changes in physical and psychological health
as perceived by the child's carer [3]. The results demonstrated that 90 of the children (34%) suffered from behavioural
changes, lasting for more than one year following their recovery from the acute stages
of Kawasaki disease. These behavioural problems were significant enough to lead to
consultation with an educational psychologist, clinical psychologist or a GP. The
behavioural problems recognised in the data included hyperactivity, decreased concentration,
increased aggression and emotional lability.

Based on these initial results, we therefore set out to investigate these behavioural
difficulties in a more detailed and quantitative fashion within a British Kawasaki
disease patient cohort.

There is nothing in the current management protocol that is aimed at addressing behavioural
difficulties, nor in the advice given to parents. Finding a significant correlation
between Kawasaki disease and behavioural sequelae would provide the basis for an important
added dimension in the long-term management of the disease. We would hope to provide
a greater insight and awareness into behavioural sequelae, which would lead to earlier
referrals to a child psychologist where necessary, more specific advice to the parents
on how best to manage their child as well as providing reassurance that the child's
behavioural difficulties may be within the normal sequelae of Kawasaki disease.

Methods

A retrospective cohort study was selected as the most appropriate method in view of
the uncommon frequency of Kawasaki disease within the UK population. Parents of children
who had been seen in clinic between 1995 – 2001 were contacted by telephone and informed
verbal consent gained. When parents could not be contacted by phone, a detailed covering
letter explained the nature of the research was sent out and parents were invited
to respond. The study was approved by the Local Ethics Committee.

The Kawasaki disease patient group (KD group)

Inclusion criteria for this stage of the research were: (a) all patients aged under
18 years at time of diagnosis and at the time of the study were between 3 to 18 years
old; (b) A diagnosis of KD formally having been reached according to the criteria
in table 1; (c) sufficient level of English spoken by parent/carer to understand questionnaires;
and (d) no history of CNS dysfunction unrelated to KD, or any other history of severe
illness.

112 sets of questionnaires were sent out to parents. 77 questionnaires were received
and 65 were suitable for inclusion according to our predetermined criteria.

Controls

Two control groups with different characteristics were used. The first consisted of
previous hospital inpatients who had stayed in hospital for a short period and undergone
a cardiac catheterisation, with follow-up at regular intervals. This group was chosen
in order to control for the effects of a hospital stay on child behaviour. Patients
who had subsequently progressed to surgery, or suffered from an unrelated CNS disorder
or other chronic illness were not deemed suitable for inclusion. These controls were
matched to the KD group, as best as possible, according to age and sex. 47 sets of
questionnaires were sent out and 23 were returned completed.

The second control group consisted of siblings of the KD group matched for age and
sex, as best as possible. This control group was selected in order to control for
the influence of genetics and environment on child behaviour. 31 sets of questionnaires
were sent out and 17 were returned.

Data collection instruments

Mothers of patients were sent out a series of psychological screening questionnaires
for behavioural difficulties, which they were invited to complete. The questionnaire
set comprised: the Child Behaviour Check List – CBCL/4–18 (Achenbach 1991) [13]; Strengths & Difficulties Questionnaire (Goodman 1997) [14], and the Parenting Stress Index – PSI, (Abidin 1983) [15]. A general information sheet was also devised for inclusion with the questionnaires.

The Child Behaviour Check List (CBCL) tests the parental reports of a child's competencies
and quantifies behavioural and emotional problems along predetermined categories.
It has a one week test-retest reliability of r = 0.93 [13]. The CBCL was used to obtain standardised reports from parents on behavioural and
emotional problems for their children. The CBCL contains 120 problems items and measures
in two broad categories: Internalising problems (consisting of the scales: anxious/depressed,
somatic complaints and withdrawn behaviour) and Externalising complaints (aggressive,
and delinquent behaviour). Additional scales of social problems, thought problems
and attention problems are also included.

The parenting stress index (PSI) short form is designed to measure stresses occurring
within the parent-child relationship and provides insight as to whether any difficulties
originate from the parent, the child or their interaction. It uses the following categories;
Total stress, Parental distress, Parent child dysfunctional interaction, and Difficult
child. Also, scores for defensive responding were recorded.

The Strengths and Difficulties Questionnaire (SDQ), looks at behavioural, emotional
and/or relationship difficulties in children as well as a positive category that rates
social strengths and interactions. The SDQ provides scores across 5 subscales; conduct,
hyperactivity, emotional, peer, and prosocial problems. It also generates a total
difficulty score.

Statistical analysis

One-way analyses of variance (ANOVA) were conducted on each measure, with Bonferoni
post hoc testing to examine the differences between the groups. Fisher's Exact Test
was also employed to test the strength of a trend within the groups. Means for each
measure and standard errors are given in Table 2.

Results

When asked by a single question, 56% of the Kawasaki disease patient cohort were reported
to be experiencing minor to severe difficulties: emotionally, behaviourally or socially.
This compared with 35% of hospital controls and 46% of sibling controls. Looking at
the scores on the Child Behaviour Check List (CBCL), the KD group consistently achieved
higher mean behavioural scores than the two control groups within all categories.
(Table 2).

Significantly higher behavioural scores were attained by the KD group within the withdrawn
(P = 0.045) and somatic (P = 0.030) categories, when compared with the sibling controls
(Table 3). This suggests a greater tendency towards internalising behaviour within the KD
group. Indeed, 40% of the KD group fell within the clinical or borderline range for
internalising problems, compared with 18.2% of the hospital controls and 12.5% of
the sibling controls (FE = 0.040). No significant differences between the groups were
found for externalising problems. The KD group was found to have significantly higher
behavioural scores on the thought problem category of the CBCL compared with the sibling
control group (P = 0.006). Thought problems reported included obsessions, compulsions
as well as strange behaviour. Results from the social and schooling categories of
the CBCL did not suggest any significant differences between the three groups.

Table 3. Selected results, including all that were significant, from the scores to the questionnaires.
FE = Fisher's exact test; SEM = Standard Error of Mean; † indicates P values less
than 0.05 * indicates which control groups differed significantly (P < 0.05) from
the KD group (see text for p values)

Scores on the Strengths and Difficulties Questionnaire showed the KD group achieving
higher mean scores than both control groups within the four negative categories of
conduct, peer, emotional and hyperactivity. Along the positive prosocial category
(rating social strengths and interactions) the KD group achieved a lower mean score
than both the control groups. The KD group were significantly less helpful and considerate
(prosocial category) than the hospital control group (P = 0.045). The KD group also
experienced significantly more problems associated with their conduct such as temper
tantrums, disobedience and argumentative behaviour when compared with the hospital
control group (P = 0.030). Greater total behavioural difficulties experienced within
the KD group when compared to the hospital controls were also demonstrated (P = 0.048).

On the Parental Stress Index, the KD group achieved greater mean scores compared to
the control groups. However, the differences fell short of significance. There may
be a trend here towards a 'difficult' child being the main source of stress within
the parent-child relationship (P = 0.084), but further research is required to confirm
this.

No significant differences were shown between the hospital control and the sibling
control groups within any of the questionnaires.

13 patients within the KD group were documented as suffering or having suffered from
coronary artery dilatation or aneurysms secondary to their Kawasaki disease. No significant
differences or trends to significance were shown when comparing the mean behavioural
scores of the KD group with dilatations/aneurysms and the KD group without dilatations/aneurysms.

Furthermore, no significant differences or values approaching significance were demonstrated
when comparing age of onset of Kawasaki disease with mean behavioural scores.

Discussion

Our initial indications that a significant number of children experience behavioural
sequelae in the short to medium-term post Kawasaki disease was confirmed by more detailed
investigation. The KD group showed higher scores on measures of behavioural and emotional
difficulties when compared with both control groups, with the emergence of significant
differences demonstrated between the KD group and the controls across various categories
of the questionnaires. The CBCL showed these significant differences to exist between
the KD group and the sibling control group, whereas the SDQ showed significant differences
between the KD and the hospital control group.

Like King et al. (2000) [7], we have shown a strong preponderance towards problems of an internalising nature
within the KD group. 40% of the KD group were shown to have internalising scores in
the clinical or borderline-clinical range, representing an incidence greater than
twice that of the control groups. In line with this, significantly higher scores were
attained by the KD group compared to sibling controls within the internalising sub-categories
of somatic problems and withdrawn traits. However, unlike King et al., our results
also highlight further difficulties relating to thought and conduct existing within
the KD group.

Importantly for parents, no significant differences were demonstrated between the
groups with regard to participation in activities and hobbies, social interaction
or performance at school. This, hopefully could form the basis of some reassuring
parental advice.

However, despite the lack of any proven link between adverse effects on the child's
overall social and academic performance, the high incidence of clinical and borderline-clinical
internalising behaviour should make the paediatrician aware of the potential need
for referral to a clinical psychologist during long term management. On account of
the fact that internalising behaviour can be harder to detect than overt externalising
traits, some simple screening questions into the child's behaviour should be posed
to the parents during long-term follow up of Kawasaki disease.

This study has a few potential sources of bias. The relatively low return rate of
the questionnaires raises the possibility of self selection bias. Bias originating
from the parent answers to the questionnaires may also exist. Kawasaki disease is
a relative rare disease with the potential for serious cardiac complications. The
associated fears and anxieties likely to be experienced by the parents may serve to
exaggerate any observed behavioural difficulties in the minds of the parents. This
would be reflected in higher than expected behavioural scores. However, the CBCL has
been argued to mitigate this bias and moreover, Green et al (1998) suggest that the
CBCL is in fact intrinsically conservative in discriminating mild emotional and behavioural
problems [16]. The relatively small size of the groups, especially the controls, may have limited
the extent of the significant behavioural and emotional problems seen, and we would
therefore expect to see more significant results emerge should the size of the groups
be expanded.

Pathological associations

Kawasaki disease is a systemic vasculitis which seems to have a predilection to coronary
arteries, although it has also been shown to affect the cerebral arteries. Evidence
suggesting the nature of the consequences arising from the cerebral vasculopathy has
come from a single-photon emission computed-tomography study carried out on 21 children
in Japan by Ichiyama and Nishikawa. They were able to demonstrate localised cerebral
hypoperfusion occurring in 29% of the patients during the acute phase of Kawasaki
disease [17].

Systemic lupus erythematous is also a multi-organ systemic vasculitis, which is known
to affect the cerebral nervous system (CNS), causing various neuropsychiatric symptoms
[18,19]. Multiple areas of hypoperfusion have been shown on SPECT studies of lupus patients
positive for neuropsychiatric symptoms [20]. Interestingly, one study of 35 patients by Colamussi et al. (1995) found that in
the absence of neuropsychiatric symptoms, uptake was normal in nearly all of the patients,
whereas hypoperfusion was demonstrated in most patients with severe neuropsychiatric
sequelae [21].

It is suggested that these areas of hypoperfusion documented within lupus and Kawasaki
disease may be caused by a process of cerebral vasculitis resulting in patchy ischaemic
areas. The damage to the CNS which is likely to arise may then alter neurological
function for some time after the acute phase of the illness, and this would certainly
provide one reasonable explanation for the behavioural difficulties that have been
shown to persist in the medium to long-term.

Indeed, supporting evidence comes from Suzuki et al, (2000) who suggested that the
remodelling of coronary aneurysms is a process that continues for many years after
the onset of the disease [22]. One might surmise that continued behavioural problems may be the result of a parallel
remodelling process occurring in the brain.

Thus, the evidence of CNS pathology adds further weight to our belief that the behavioural
changes arise secondary to a cerebral vasculopathy, and are not merely due to the
psychological complications of an acute severe illness.

Further experimental evidence

In order to further investigate any identifiable CNS pathology affecting the brain,
active or otherwise, we have performed PET (glucose and ammonium) and MRI scans on
7 post Kawasaki disease patients with severe behavioural difficulties (Table 4). In all seven cases these were carried out at least 6 months after their last episode
of Kawasaki disease. Three of these patients were reported to have slightly reduced
uptake of tracer, occurring within the occipital lobes, although other areas were
also affected in two of the cases. Although these minimal changes are of uncertain
significance, they could represent resolving areas of cerebral hypoperfusion secondary
to cerebral vasculitis that occurred during the acute phase of the disease. An ethically
approved study with a larger patient base would be the next step to investigate these
changes further.

Summary

In conclusion, we have shown significant behavioural sequelae can occur following
acute Kawasaki disease. Therefore, the paediatrician should bear in mind the potential
need for long term follow up of Kawasaki disease patients in clinic even in the absence
of coronary artery aneurysms. Parents can be told that behavioural difficulties experienced
may be within the normal sequelae of the disease process and they can be reassured
that they do not appear to affect school performance to any significant degree. However,
a few probing questions should be asked to flesh out other possible causes before
any difficulties are attributed to Kawasaki disease. The paediatrician should consider
referral to a clinical psychologist where necessary. This may indeed prove to be a
common requirement in long-term management, when it is considered that 40% of the
KD group in this study fell within the clinical or borderline-clinical range for internalising
problems.

Future research should examine the behavioural difficulties in greater detail, employing
formal neuropsychiatric testing. Additionally, further research in this area is required
to rule out other possible causes of behavioural sequelae. In particular, standard
treatment with aspirin and intravenous gammaglobulin should be eliminated as potential
aetiological factors.

Acknowledgements

We are very grateful to the Kawasaki disease support group for their assistance with
the funding of this study. We would also like to warmly thank the families of patients
who have helped with this study, as well as their clinicians for referring patients
to the Kawasaki Clinic.

References

Kawasaki T: Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation
of the fingers and toes in children (Japanese).